# Nuclear import of beta-Catenin in Wnt-signaling

> **NIH NIH R21** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $254,250

## Abstract

Project Summary
 Wnt/Wingless (Wg)-signaling plays important roles in intercellular signaling in all metazoan organisms. It
functions in many critical processes, such as organ patterning, growth control, cell polarity, and stem cell
maintenance. When deregulated it is linked to diseases ranging from congenital heart disease and aberrant
vasculogenesis to cancer. Recent studies in my lab have shown that Intraflagellar Transport complex A (IFT-A)
proteins modulate canonical Wnt/Wg-signaling independently of the ciliary role of IFTs. We demonstrated that
they do so together with Kinesin2 (as they do in ciliary functions) and promote nuclear translocation of β-
catenin upon Wnt-pathway activation and act downstream of β-catenin stabilization. Kinesin-2 and IFT-A
proteins act as a complex during Wg-signaling in Drosophila and mammals. Mutants of both, Kinesin 2 and
IFT-A, affect Wg/Wnt-signaling in the same manner, and they interact genetically and physically. Kap3, a
kinesin associated protein that serves as the bridging factor between Kinesin 2 and IFT-A in ciliary function is
also required in the same manner and is involved in the formation of a physical complex of Kinesin 2-Kap3-
IFTs. The IFT-A protein IFT140 then directly binds to β-catenin, called Armadillo/Arm in Drosophila. Upon
pathway stimulation by Wg/Wnt and resulting pathway activation, all these factors co-localize with each other
and β-catenin, and bind together to micro-tubules (MTs). Single or double mutant cells for Kinesin-2, IFT-As, or
Kap3 fail to properly activate Wg/Wnt-signaling targets in both Drosophila and MEFs. In addition, axin double
mutant backgrounds with IFT-A or Kinesin-2 reveal high levels of cytoplasmic Arm/β-catenin but fail to activate
Wg/Wnt targets, due to reduced nuclear β-catenin localization. These data indicate that the Kinesin-2/IFT-A
complex promotes nuclear localization of Arm/β-catenin by protecting it from a cytoplasmic tether/inhibitor. We
have thus identified a mechanistic function of the Kinesin-2/IFT-A complex in Wnt-signaling, independent of
their role in the cilium. As the associated mechanism(s) are conserved in mammalian cells, these observations
are potentially amenable to drug treatment. However, several questions remain: (i) How is the Kinesin-2/IFT-A
complex promoting nuclear localization; our data suggest it is by movement along microtubules, but this needs
to be refined; and (ii) what is the factor that competes with IFT140 binding to Arm/β-catenin and serves an
`inhibitory' function for Arm/β-catenin nuclear localization. We will address in Aim 1 the cell biology of this
mechanism using an elegant ex vivo Wnt-signaling system, and Aim 2 is tailored to identify antagonistic
factor(s) that compete with IFT140 binding. Our preliminary data suggest that this knowledge can serve as an
entry-point for new drug development to inhibit overactive Wnt/β-catenin signaling. Thus, information acquired
in this application will advance our mechanistic ...

## Key facts

- **NIH application ID:** 9917359
- **Project number:** 1R21HD095141-01A1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Marek Mlodzik
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $254,250
- **Award type:** 1
- **Project period:** 2020-02-03 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9917359

## Citation

> US National Institutes of Health, RePORTER application 9917359, Nuclear import of beta-Catenin in Wnt-signaling (1R21HD095141-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9917359. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*